Animal evidence considered in determination of cannabis smoke and Δ9-tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action

This review summarizes the most common potential pathways of neurodevelopmental toxicity due to perinatal exposure to Δ⁹-tetrahydrocannabinol (Δ⁹-THC) that lead to behavioral and other adverse outcomes (AOs). This is Part III in a set of reviews highlighting the animal-derived data considered by California’s Developmental and Reproductive Toxicant Identification Committee (DARTIC) in 2019. The Hazard Identification Document (HID) provided to the DARTIC included a summary of human, whole animal, and mechanistic data on the neurodevelopmental toxicity of cannabis smoke and Δ⁹-THC. The literature search for mechanistic data has been updated through 2020. We focus on mechanistic pathways relating to behavioral and other neurodevelopmental outcomes of perinatal exposure to Δ⁹-THC. The endocannabinoid system (EC system) plays a crucial role in many processes involved in neurodevelopment and exposure to Δ⁹-THC can alter these processes. Whole animal studies report changes in cognitive ability, behavior, and motor function after prenatal exposure to Δ⁹-THC. Findings from mechanistic studies add to this evidence and further provide information regarding the pathways leading to these outcomes. Neuromechanistic studies can bridge the gaps between molecular initiating events and apical neurodevelopmental endpoints caused by a chemical. They offer insight into potential alterations in the same pathways by other chemicals that can also result in AOs. Studies of cannabinoid receptor agonist-induced molecular alterations and provide deep biological plausibility at the mechanistic level for the cognitive, behavioral, and motor impairments observed in animal studies after perinatal exposure to Δ⁹-THC.